Combined PET and Microdialysis for In Vivo Assessment of Intracellular Drug Pharmacokinetics in Humans

Abstract

Because many drugs possess an intracellular site of action, the knowledge of intracellular concentration−time profiles is desirable. In the present study, PET, which measures total (i.e., intracellular, extracellular, and intravascular) concentrations of radiolabeled drugs in tissue, and microdialysis, which determines unbound drug concentrations in the extracellular space fluid of tissue, were combined to describe the intracellular pharmacokinetics of a model compound—that is, the ¹⁸F-labeled antibiotic ¹⁸F-ciprofloxacin—in vivo in humans. Methods: Ten healthy male volunteers received a mixture of 687 ± 50 MBq of ¹⁸F-ciprofloxacin and 200 mg of unlabeled ciprofloxacin as an intravenous bolus infusion over 10 min. The pharmacokinetics of ciprofloxacin in skeletal muscle tissue were assessed by means of combined PET and in vivo microdialysis for 5 h after drug administration. A 3-compartment pharmacokinetic model was fitted to the tissue concentration−time profiles of ciprofloxacin measured by PET to estimate the rate constants of ciprofloxacin uptake and transport. Results: In muscle tissue, mean total and extracellular peak concentration (C_max) values of ciprofloxacin of 1.8 ± 0.4 μg/mL and 0.7 ± 0.2 μg/mL were attained at 95 ± 34 min and 48 ± 20 min after drug administration, respectively. The extracellular-to-intracellular exchange appeared to be very fast, with an estimated rate constant k₃ of 1.69 ± 0.25 min⁻¹. An intracellular-to-extracellular concentration ratio (C_intra/C_extra) of 3.2 ± 0.8 was reached at 110 min after injection and followed by sustained intracellular retention of the antibiotic for the remainder of the experiment. The predicted extracellular concentration−time profiles from the compartmental modeling were in good agreement with the measured microdialysis data. Conclusion: The results obtained in the present study were in accordance with previous in vitro data describing cellular ciprofloxacin uptake and retention. The presently used PET/microdialysis combination might be useful during research and development of new drugs, for which knowledge of intracellular concentrations is of interest.